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Clayton`s screen debut came in 1909, in a short called Justified. In 1912 she made her feature length debut in For the Love of a Girl. The film was directed by Barry O`Neil. Ethel was cast with Harry Myers, Charles Arthur, and Peter Lang. She was also directed by William Demille, Robert G. Vignola, George Melford, Donald Crisp, Dallas M. Fitzgerald, and Clifford Sanforth.

Like many silent film actors Clayton`s career was hurt by the coming of sound to motion pictures. She continued her career in small parts in movies until she retired in 1948. Her screen credits number more than 180.

In 1931 Clayton obtained a California Superior Court order enjoining her former business partner, W.L. Rucker, from disposing of 316 pearls. Clayton and Rucker agreed to purchase a cosmetics business and the pearls had been entrusted to Rucker to raise money. The deal fell through and he refused to return the jewels. Rucker admitted to possessing the pearls but claimed they had been pledged as security for a $125 loan. The pearls were valued at $20,000.

She was first married to actor Joseph Kaufman until his death in 1918 in the Spanish Influenza epidemic. She later married silent film actor and former star Ian Keith twice and they divorced twice. In both cases Ethel Clayton cited cruelty and excessive drinking. Clayton and Keith were first married in Minneapolis in 1928 and first separated on January 13, 1931.

hel Clayton died on June 6, 1966 at St. John`s Hospital in Oxnard, California, aged 83.

The actress has a star on the Hollywood Walk of Fame. She was buried at Ivy Lawn Memorial Park in Ventura, California.